Reactions Catalyzed by Anion Exchange Resins J
J
KNOEVENAGEL CONDENSATION MELVIN J. ASTLE AND JOEL A. ZASLOWSKY' Case Institute of Technology, Cleveland, Ohio
.
A
b
XIOX exchange resins such as Amberlite IR-4B, Deacidite, and Amberlite IRA-400 are excellent catalystsfor promoting Knoevenagel condensations between aldehydes and esters, such as ethyl cyanoacetate, ethyl acetoacetate, and diethyl malonate. Condensations with diethyl malonate cannot be accomplished a t room temperature but may be carried out by refluxing in benzene solution. The benzene removes the water as an azeotrope as fast as formed. Condensation with ethyl cyanoacetate can be effected by agitating the aldehyde and ester a t room temperature in the presence of the anion exchange resin. Those reactions involving ethyl acetoacetate can be carried out by either of the above-mentioned methods. Ion exchange resins may be considered to be insoluble acids or bases, and consequently might be expected to promote reactions which are catalyzed by conventional acids or bases. Cation exchange resins in which the functional group is SOaH are strong acids while those in which the functional group is COOH are weak acids. Similarly anion exchange resins are strong or weak bases, depending upon whether the functional group is a quaternary ammonium or an amino group. Cation exchange resins have been used successfully as catalysts in the following reactions: esterification (20, 26), ester hydrolysis ( l a , $6, 27), sucrose inversion ( 2 6 ) ,alcohol dehydration (26),and acetal formation (86). Only a few examples of reactions catalyzed by anion exchange resins are reported in the literature. Jenny (14) reported that anion exchange resins catalyzed the mutarotation of glucoseand Galat (11,18)converted nicotinonitrile in good yields to nicotinamide by refluxing with a strongly basic anion exchange resin. The advantages of solid, substantially insoluble catalysts are that the separation problems are manifestly simpler, the same catalyst can be used repeatedly, and sensitive molecules can, in some cases, be reacted without polymerization or other side reactions-e.g., furfuryl alcohol can be esterified with acetic acid. The Knoevenagel condensation has been studied quite extensively by Cope and other workers (7-9) using amines as catalysts. This reaction was therefore chosen for further investigation using anion exchange resins in place of the more conventional catalysts. This reaction also presented the opportunity to observe the catalytic activity of ion exchange resins in systems which are essentially nonaqueous. The Knoevenagel reaction involves the condensation of aldehydes or ketones with compounds containing active hydrogen, such as ethyl acetoacetate, ethyl cyanoacetate, and diethyl malonate. These reactions are illustrated in the following equations :
R-CHO
+ CH,-CO-CH,-COOCzH, + CHs-CO-C-COOC2HS II
+ HBO
613-R 1
Present address, Mathieson Chemical Gorp., Niagara Falls, N. Y .
(1)
R-CEO
-I-NC-CHZ-COOCZH~ +
NC-C-COOC2H,
+ HzO
(2)
+ HzO
(3)
8H--R /COOCzHt,
R-CHO
+ HzC
+
\COOC>Hs /COOC2Ho R-CH=C \COOC2Hs Cope found that piperidine and piperidine acetate were particularly effective catalysts for the condensation of aldehydes with ethyl acetoacetate. It was also shown by Cope that the Knoevenagel reaction was reversible, and better yields were obtained in many cases by using a water separator to remove the water formed during the reaction. This method was analogous t o the esterification work of Sussman (26) using cationic exchange resins. Although there is some evidence for a noncatalyxed reaction, this doeR not a-count for more than a trace of the product formed in these reactions ( 7 ) . I n this investigation, several commercially available aldehydes were condensed with ethyl acetoacetate, ethyl cyanoacetate, and diethll malonate (Table I). EXPERIMENTAL
Two general procedures were employed in effecting the Knoevenagel condensation. These procedures will be described below as A and B. PROCEDURE A. To effect condensations by this method 0.5 mole of ethyl acetoacetate or ethyl cyanoacetate was agitated at room temperature with slightly more than equimolar amounts of freshly distilled aldehyde in the presence of 15 to 30 grams oi air-dried resin. The time required to effect maximum yield by this method depends upon the aldehyde and ester employed, Agitation was achieved by means of a shaking device (Burrell), inasmuch as the use of a stirrer caused considerable physical deterioration of the resin. At the end of the reaction period the solution was decanted and the suspended resin was removed by filtration. The resin was then rinsed with benzene, air-dried, and re-used. The reaction mixture was distilled to remove unreacted aldehyde and heated where applicable to approximately 180' C. to effect the dehydration of the aldol which is formed as a byproduct. The residue was fractionally distilled a t reduced pressure. PROCEDURE B. This method involved reflux in the presence of benzene. The same quantities of reactants as in method A were placed in a flask equipped with reflux condenser and water separator together with 100 to 150 ml. of benzene. When rcflux
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INDUSTRIAL AND ENGINEERING CHEMISTRY
Vol. 44, No. 12
Table I1 lists several specific runs attempted with butyrReaction aldehyde and isobutyraldeTime, Product Yield, 97, Method Hr. B.P. C. Reference hJ-de. Butylidene ethyl acetoacetate 50 A 10-24 124-128 (23 mm.) (8) The efficiency of the strongly Propylidene ethyl acetoacetate 37 A 24 103-106 (11mm.) Nem cpd. basic Smberlite 1~A-400 and Isobutylidene ethyl acetoacetate 60 B 10-15 113-117 (17 mm.) (16) 65 A 10-24 Don-ex 1 is seen to be less than B 6 130-132 (10 mm.) New cpd. Hexylidene ethyl acetoacetate that of Deacidite. Deacidite 6,: 4_2 2-Ethylbutylidene ethyl aceto64 B 8 122-123 (11 mm.) (8) acetate, IR-4B, IRl4B acetate, acetate 57 A 72 Benzylidene ethyl acetoacetate" 40 B 4 164-167 (10mm.)b (16, 2 5 ) and Duolite A-4. This could Heptylidene ethyl acetoacetate 51 A 60 133-136 (8 mm.) (16) probably be attributed to the Ethylidene ethyl acetoacetate 51 Ac 22 106-110 (23 mm.) (16, 24) 2-Ethylhexylidene ethyl aceto58 B 24 124-128 (14 mm.) (8) lower capacity of these resins acetate 52 A 202 Hexylidene diethyl malonate 33 B il 146-148 (10 mm.) (9) (the strong bases have a 62 A 30 140-143 7 mm.) (10.2%) Heptylidene ethyl cyanoacetate capacity of about 2.5 meq. per 54 A 22 142-144 {13 mm.) Kew cpd. Hexylidene ethyl cyanoacetate New cpd. 70 A 30 140-141 (9 mm.) 2-Ethvlhexvlidene ethyl . cyano. gram, while the weak bases acetate 83 A 20 118-123 (9 mm.) iXew cpd. 2-Ethylbutylidene ethyl cyanohave capacities in the neighboracetate hood of 1 meq. per gram). 42 A Furfurylidene ethyl acetoace46 155-159 (9 mm.) e (16) tated The efficiency of the weakly 5 P r a t t a n d Werble (86)did not obtain a solid product; they recognized the possibility of cis-trans isomerism. basic resins is further enhanccd A solid product was not obtained in t h e present work. by the undiminished catalysis b hlelline uoint. 60' to 61' C. ( 7 ) . 0 100 m1:beneene were employed as a diluent. of the carboxylic acid-neutrald Two products were isolated-a solid melting'at 61° t o 62' C. and %liquid. 10 days were required for crystallisation; possibly cis-trans isomers: analysis of 1iq;id gave WOEt: found 21.4, calcd. 21.6; Knoevenagel reported a ized form of these resins. The %month crystallization period. strongly basic resins are not 6 Melting point, 61' to 62' C. recommended for long-term use. A yet unpublished work by the authors on the aldol condensations indicates that the strongly basic resins are rapidly commenced the water was removed from the reaction mixture deactivated by the addition of acetic acid or by exposure to as.fast as it was formed. The mixture was refluxed a t least as long as water was being evolved. The reaction mixture was the atmosphere for several days. The latter observation has been verified in this Fork. worked up in a manner similar to method A. The above facts are in agreement x i t h the known catalytic This method was the most successful with aldehydes which do activity of the carboxylic acid salts of weak bases ( 7 - Q ) . not undergo the aldol condensation too readily-e.g., alpha-subProcedure B is preferred for condensing high molecular weight stituted aldehydes, aromatic aldehydes, and long-chain aliphatic and alpha-substituted aldehydes with ethyl acetoacetates. aldehydes, such as hexaldehyde. These condensations iyhen conducted at room temperature Yields are based upon the amount of ester converted to product, (method A) require very long reaction times. Thr amount of Le., the ratio of product to ester added. by-product and residue formed during the condensations of The resins employed were all of the commercial type (20 to 50 alpha-substituted aldehydes with ethyl acetoacetate is almost mesh) and were used pithout any screening for particle size or nil. This has been attributed to the sluggishness of the competing determination of the water content of the air-dried resins. I t aldol condensation of these aldehydes and t o the inability for is recognized that these factors do probably affect the efficiency the aldol to dehydrate in an essentially unreversible manner. of the catalysts, but they are being neglected in this study for Condensations of aldehydes with ethyl cyanoacetate proceed simplicity. It is not believed that these factors are too important more rapidly and usually in better yield than the corresponding in synthetic work. condensations with ethyl acetoacetate. Method A mas excluAmberlite IR-4B, Amberlite IR-45, Deacidite, and Duolite 8-4 sively used for the reactions of ethyl cyanoacetate. Even are weakly basic resins whose basicity is attributed t o amino unreactive aldehydes gave good yields by this method. groups. These are shipped in the basic form (except Duolite The condensation of diethyl malonate with aldehydes proceeds A-4), and simply required rinsing with water and air drying before only by method B, as does the condensation of benzaldehyde n ith use. hmberlite IRA-400 and Dowex I are strong bases and are ethyl acetoacetate. shipped as the chloride salt. These resins must be regenerated before use. The regeneration x a s effected by washing with 5yo sodium hydroxide ( 5 to 6 times the volume of resin) in a Buchner funnel. The resins n ere then rinsed x i t h distilled water TABLE11. CONDENSATION O F ISOBUTYRALDEHYDE -4ND BUTYRuntil the washings were neutral. The resins were air-dried and ALDEHYDE WITH ETHYL ACETOACETATE (METHODA). employed in a manner similar to the weakly basic resins. Reaction G. Catalyst/ Time. I n some cases the weakly basic resins were converted to their Catalyst Mole Aldehyde Hours Yield acetate salts bv washing- with glacial acetic acid. The excess ISOBUTYRALDEHYDE acid was filtered off, and the resins were washed with acetone and Deacidite acetate 40 10 48 air dried. Deacidite acetate 40 24 51
TABLE I.
C O M P O U N D S P R E P A R E D BY
__
KNOEVENAGEL CONDENSSTIONS
__
I
DISCUSSION O F RESULTS
The main purpose of this investigation was t o determine whether or not anion pxchange resins are effective catalysts for the Knoevenagel condensation and to determine n-hat yields (as previously defined) can be obtained by the methods developed. It was a l ~ oof great interest to determine the catalytic life of these resins. Table I lists the various compounds prepared and gives the yields obtained in representative runs by the two general methods used.
Deacidite acetate Deacidite IR-4B
30 40 45
BUTYRALDEHIDE Deacidite acetate 25 IRA-400 45 IRA-400 45 Deacidite 45 Douex 1 40 IR-4B 40 Duolite A-4 45 I R - I B acetate 40 I n each case 0.56 mole of the aldehyde a n d 0.5 ployed.
15
24 48
51 55 54
17 49 18 31 68 49 24 49 22 31 30 48 24 50 24 50 mole of ester were em-
December 1952
I N D U S T R I A L A N D E N G I N E E R I N G CHEMISTRY
TABLE 111. TYPICAL REACTIONS~ USING THE SAME CATALYST WITH No TREATMENT BETWEEN RUNS (25 grams of Deacidite) Previous No..of Reaction Timeb, Runs Hr. WITH ETHYLACETOACETATE
Aldehydea
Yield, %
3 6 7
Isobutyraldehyde Isobutyraldehyde 2-Ethyl butyraldehyde 2-Ethyl butyraldehyde Hexaldehyde Butyraldehyde Butyraldehyde
15 53 24 50 24 16 7 72 41 11 42 45 18 66 54 21 24 49 WITH ETHYLCYANOACETATE 2-Ethyl butyraldehyde 30 19 83 Hexaldehyde 31 9 44 Hexaldehyde 32 23 54 a I n each case 0.55 mole of the aldehyde and 0.5 mole of the ester were used. b All runs were made a t room temperature.
parently required more time to effect maximum conversions and are easily inactivated. This inactivation can be brought about by the presence of acids such as might be found in the aldehydes or carbon dioxide. The most generally satisfactory resins investigated were Deacidite and Amberlite IR-4B. (Other weakly basic resins, such as Duolite-A-4, are also satisfactory but have not been investigated so thoroughly.) Deacidite and Amberlite IR-4B were converted to their acetate salts and these treated resins were found t o be as effective as the free base. Although anion exchange resins are not considered to be heat stable there was no loss of activity of Deacidite or Amberlite IR-4B after several runs a t the reflux temperature of benzene. The data here submitted suggest that IR-4B and Deacidite might be used in continuous operations using columns packed with resin. Such procedures were not attempted in the investigation of the Knoevenagel condensation, but the aldol condensation of butyraldehyde has been accomplished using the above techniques. Compounds which have not been previously reported in the literature are given in the following table, together with some physical and chemical properties:
Table I11 records but one of a series of inactivation studies carried out with the weakly basic resins. This data would indicate that the weakly basic resins do not undergo inactivation even after many runs. A few general observations can be made concerning these Boiling Pt., Compound c. reactions: Most of the anion exchange resins Were equally Propylidene ethyl aceto103-106 O
acetate Hexylidene ethyl acetoacetate 2-Ethylbutylidene ethyl cyanoacetate 2-Ethylhexylidene ethyl cyanoacetate Hexylidene ethyl cyanoacetate
effective in promoting the Xnoevenagel c o n d e n s a t i o n . IR-45 gave much poorer conversion after several runs than
the Other resins investigated‘ The strongly basic resins ap-
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(11 mm.) 130-132 (10mm.) 122-123 ( 8 . 5 mm.) 140-141 (9 mm.) 142-144 (13 mm.)
Analysis Hydrogen, % Calcd. Found
Refractive Index
Carbon, % Calcd. Found’
n”$, 1 4500
63.46
63.4
8.23
8.01
n2,, 1.4571
67.92
67.83
9.42
9.17
...
..
..
..
7.18
6 89
nge, 1.4522
...
... ... ...
..
rigs, 1.4541
..
..
6.25
5.95
..
..
7.18
7.01
n2,6,1.4535
...
Nitrogen. % Calcd. Found
..
..
(Reactions Catalyzed by Anion Exchange Resins)
ALDOL CONDENSATION
A
0
LDOL condensations of aldehydes can be carried out in
c
much the same manner a8 the Knoevenagel condensations. The weakly basic resins such as Amberlite IR-4B or Deacidite are more effective than the strongly basic resins because they are effective condensation catalysts even in the presence of organic acids. The aldol condensation of acetone can be readily effected with strongly basic anion exchange resins such as Amberlite IRA-400 or Dowex-1. The aldol condensation of aldehydes and ketones can be represented by the following equations:
0 2R-CHs-CH
11
OH
Base
I R-CH2-C-CHC-H I I
0
II
(4)
H R
0 2R-CH2-C-R’ 11
OHR 0
Base.+ R-cH2-A-A-J-R’ I 1
(5)
R’ H
I1
R-CH2-C=C-C-R’,
respectively.
I I
R‘ R The aldol condensation of aldehydes was first reported by Wurtz (29), who used dry hydrochloric acid, zinc chloride, sodium carbonate, and potassium carbonate as catalysts. Other catalysts reported in the literature included the alkali hydroxides, sulfites, cyanides, and acetates. Of more recent date are the investigations reporting the uses of amine salts and amino acids as catalysts for the aldol condensation (IO,13, 17). The aldol condensation is a reversible reaction, but can in many cases proceed to form a dehydrated condensation product. At low temperatures (below 25” C.), the aldol is the main reaction product; a t higher temperatures the aldol dehydrates to the unsaturated condensation product. The aldol also dehydrates spontaneously when distilled a t atmospheric pressure or when heated with an acid.
The initially formed aldol in the above cases can easily be EXPERIMENTAL
0
dehydrated to give R-CH2--C=C-C-H
I 1
H R
It
,
and
The following anion exchange resins were employed in this study: the strongly basic Amberlite IRA-400, Permutit 8, and Dowex 1; the weakly basic Deacidite, Amberlite IR-4B, and Amberlite IR-45.
